EP0727996B1 - Fenbendazole formulations - Google Patents

Fenbendazole formulations Download PDF

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Publication number
EP0727996B1
EP0727996B1 EP95901776A EP95901776A EP0727996B1 EP 0727996 B1 EP0727996 B1 EP 0727996B1 EP 95901776 A EP95901776 A EP 95901776A EP 95901776 A EP95901776 A EP 95901776A EP 0727996 B1 EP0727996 B1 EP 0727996B1
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EP
European Patent Office
Prior art keywords
weight
ppm
fenbendazole
suspension according
preservative
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Expired - Lifetime
Application number
EP95901776A
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German (de)
French (fr)
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EP0727996A4 (en
EP0727996A1 (en
Inventor
Leslie E. Kyle
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Akzo Nobel NV
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Akzo Nobel NV
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches

Definitions

  • This application relates to new and useful formulations of fenbendazole.
  • Fenbendazole is a benzimidazole carbamate compound used as a veterinary anthelmintic in many species, including poultry, swine and cattle. Fenbendazole is used to control nematodes such as Ascaridia, Heterakis and Capillaria in poultry and in swine. Fenbendazole is often administered in the feed, or in the case of poultry and swine, in the drinking water.
  • Fenbendazole is insoluble in water.
  • the aqueous suspensions of the compound have been unsatisfactory because the compound does not stay in suspension. Accordingly, there remains a need for stable aqueous suspensions of fenbendazole.
  • US-A-3954791 teaches that aqueous suspensions of anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers for parenteral administration may be prepared with the use of ethoxylated sorbitane fatty acid ester.
  • the instant invention provides an aqueous formulation of fenbendazole for drinking water administration which is stable and efficacious, does not agglomerate upon standing and wherein the fenbendazole remains in suspension after standing for twenty-four hours.
  • the formulation comprises a therapeutically effective amount of fenbendazole, a preservative, surfactant and water.
  • the preservative is an arylalkyl alcohol such as benzyl alcohol.
  • the surfactant is a polysorbate such as polyoxyethylene (20) sorbitan monoleate.
  • the fenbendazole is present in the formulation in an amount from 10% to 30% by weight, preferably from 15% to 25%, most preferably 20% by weight.
  • the preservative is one known to those in the art, preferably benzyl alcohol. It is present in an amount from 1% to 3% by weight, preferably from 1.5% to 2.5%, most preferably about 2% by weight.
  • the surfactant is a water soluble nonionic surface active agent comprised of complex esters and ester-ethers derived from hexahydric alcohols, alkylene oxides and fatty acids by adding polyoxyethylene chains to hydroxyl of sorbitol and hexitrol anhydrides (hexitans and hexides) derived from sorbitol and then partially esterifying with the common fatty adds such as lauric, palmitic, stearic and oleic.
  • these are the Tween type products known in the art.
  • the surfactant is Tween 80, known in the pharmaceutical industry as Polysorbate 80, having the chemical name polyoxyethylene (20) sorbitan mono-oleate.
  • the surfactant is present in the formulation at from 5% to 15% by weight, preferably from 7.5% to 12.5% by weight, most preferably 10%.
  • Any type of water may be used in the formulation, for example, deionized water or hard water.
  • the formulation may also contain an antifoaming agent, such as for example, simethicone emulsion USP.
  • the antifoaming agent is present in sufficient concentration to allow control of the foam which forms when the formulation of the instant invention is diluted with water.
  • the simethicone may be present at concentration of from 0.2% by weight to 1% by weight, preferably 0.5% by weight.
  • the concentrated (10% to 30% fenbendazole) formulation is diluted with water to yield a formulation where the fenbendazole is present in a concentration in the range of from 4,000 ppm to 10,000 ppm, preferably from 6,000 ppm to 10,000 ppm, most preferably 8,000 ppm.
  • This formulation is used to treat poultry with fenbendazole in the drinking water.
  • the diluted formulation is used in a proportioner or medicator as is known in the art.
  • the medicator uses for example 1 oz of the stock formulation and further dilutes with water generally in about a 1:128 ratio to obtain medicated drinking water having a fenbendazole concentration of from 45 to 80 ppm, preferably 65 ppm.
  • the "20%" formulation is diluted directly to a concentration of from 45 ppm to 80 ppm, preferably 65 ppm and used for poultry drinking water directly.
  • the concentration of the fenbendazole is calculated to provide the targeted amount of fenbendazole per body weight (BW) of the poultry being treated, preferably in the range of 1 mg to 5 mg of fenbendazole per kilogram of body weight per day in the volume of drinking water normally consumed by the poultry being treated in a 6 to 12 hour treatment period.
  • BW body weight
  • the targeted dosage is dictated by the parasitic species infection being treated and is known in the art.
  • the medicated drinking water is used to treat the poultry for 6 to 12 hour treatment periods, preferably 8 hour treatment periods on each of two to six consecutive days.
  • the concentrated solution is diluted to achieve the desired concentration so as to obtain drinking water containing an efficacious amount of fenbendazole to control helminths in swine.
  • the efficacious amount is dependent on the helminth species infection being treated and is known in the art.
  • the concentrated formulation of the invention is typically prepared by adding the preservative and surfactant to the water and stirring until dissolved. The fenbendazole is then added and the mixture is stirred until it is homogeneous.
  • the mixture is then passed through a homogenizer to obtain relatively uniform particle size distribution on the order of about 1 micron (m).
  • the homogenization is carried out by means known in the art such as for example with a rotor stator or a high pressure homogenizer.
  • the mixture is passed through until the pressure can be maintained within the range of from 9,000 to about 15,000 psig, preferably in a range of from about 12,000 psig to about 14,000 psig, most preferably within a range of about 13,000 psig.
  • the mixture is passed through at a pressure of from about 2,000 psig to about 10,000 psig, preferably within a range of from about 4,000 psig to about 8,000 psig.
  • the suspension was divided into 7 portions, A through G. Portions B to G were homogenized each using a different homogenizer or different processing conditions.
  • the viscosity of each portion was measured with a Brookfiled viscometer model RVTI, Spindle HRVI, speed 5 rpm.
  • the particle size distribution was determined by the Galai ClS-1 automated particle size analyzer with a 1° wedge prism installed in the 0-60 M range. Each sample was analyzed four times and the results were averaged.
  • the processing conditions for each sample are set forth in Table 2 along with the viscosity data for each portion.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Agricultural Chemicals And Associated Chemicals (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Lock And Its Accessories (AREA)
  • Chemical And Physical Treatments For Wood And The Like (AREA)
  • Structures Of Non-Positive Displacement Pumps (AREA)

Abstract

This application relates to an aqueous formulation of fenbendazole which is stable and efficacious, does not agglomerate upon standing and wherein the fenbendazole remains in suspension after standing for twenty-four hours.

Description

This application relates to new and useful formulations of fenbendazole.
Fenbendazole is a benzimidazole carbamate compound used as a veterinary anthelmintic in many species, including poultry, swine and cattle. Fenbendazole is used to control nematodes such as Ascaridia, Heterakis and Capillaria in poultry and in swine. Fenbendazole is often administered in the feed, or in the case of poultry and swine, in the drinking water.
Fenbendazole is insoluble in water. The aqueous suspensions of the compound have been unsatisfactory because the compound does not stay in suspension. Accordingly, there remains a need for stable aqueous suspensions of fenbendazole.
US-A-3954791 teaches that aqueous suspensions of anthelmintically active 2-carbalkoxy-amino-benzimidazole-5(6)-phenyl ethers for parenteral administration may be prepared with the use of ethoxylated sorbitane fatty acid ester.
It is an object of the present invention to provide for stable, efficacious aqueous formulations of fenbendazole, for drinking water administration.
It is further an objective of this invention to provide aqueous suspensions of fenbendazole wherein there is no agglomeration of particles or change in particle size after the suspension has been stored for a period of time.
The instant invention provides an aqueous formulation of fenbendazole for drinking water administration which is stable and efficacious, does not agglomerate upon standing and wherein the fenbendazole remains in suspension after standing for twenty-four hours.
More particularly, the formulation comprises a therapeutically effective amount of fenbendazole, a preservative, surfactant and water. Preferably the preservative is an arylalkyl alcohol such as benzyl alcohol. Preferably the surfactant is a polysorbate such as polyoxyethylene (20) sorbitan monoleate.
The fenbendazole is present in the formulation in an amount from 10% to 30% by weight, preferably from 15% to 25%, most preferably 20% by weight.
The preservative is one known to those in the art, preferably benzyl alcohol. It is present in an amount from 1% to 3% by weight, preferably from 1.5% to 2.5%, most preferably about 2% by weight.
The surfactant is a water soluble nonionic surface active agent comprised of complex esters and ester-ethers derived from hexahydric alcohols, alkylene oxides and fatty acids by adding polyoxyethylene chains to hydroxyl of sorbitol and hexitrol anhydrides (hexitans and hexides) derived from sorbitol and then partially esterifying with the common fatty adds such as lauric, palmitic, stearic and oleic. Preferably these are the Tween type products known in the art. Most preferably the surfactant is Tween 80, known in the pharmaceutical industry as Polysorbate 80, having the chemical name polyoxyethylene (20) sorbitan mono-oleate. The surfactant is present in the formulation at from 5% to 15% by weight, preferably from 7.5% to 12.5% by weight, most preferably 10%.
Any type of water may be used in the formulation, for example, deionized water or hard water.
Optionally, the formulation may also contain an antifoaming agent, such as for example, simethicone emulsion USP. The antifoaming agent is present in sufficient concentration to allow control of the foam which forms when the formulation of the instant invention is diluted with water. In the instant invention the simethicone may be present at concentration of from 0.2% by weight to 1% by weight, preferably 0.5% by weight.
In another embodiment of this invention the concentrated (10% to 30% fenbendazole) formulation is diluted with water to yield a formulation where the fenbendazole is present in a concentration in the range of from 4,000 ppm to 10,000 ppm, preferably from 6,000 ppm to 10,000 ppm, most preferably 8,000 ppm. This formulation is used to treat poultry with fenbendazole in the drinking water. The diluted formulation is used in a proportioner or medicator as is known in the art. The medicator uses for example 1 oz of the stock formulation and further dilutes with water generally in about a 1:128 ratio to obtain medicated drinking water having a fenbendazole concentration of from 45 to 80 ppm, preferably 65 ppm. Alternatively, the "20%" formulation is diluted directly to a concentration of from 45 ppm to 80 ppm, preferably 65 ppm and used for poultry drinking water directly.
The concentration of the fenbendazole is calculated to provide the targeted amount of fenbendazole per body weight (BW) of the poultry being treated, preferably in the range of 1 mg to 5 mg of fenbendazole per kilogram of body weight per day in the volume of drinking water normally consumed by the poultry being treated in a 6 to 12 hour treatment period. The targeted dosage is dictated by the parasitic species infection being treated and is known in the art.
The medicated drinking water is used to treat the poultry for 6 to 12 hour treatment periods, preferably 8 hour treatment periods on each of two to six consecutive days.
Of course, to treat swine the concentrated solution is diluted to achieve the desired concentration so as to obtain drinking water containing an efficacious amount of fenbendazole to control helminths in swine. The efficacious amount is dependent on the helminth species infection being treated and is known in the art.
The concentrated formulation of the invention is typically prepared by adding the preservative and surfactant to the water and stirring until dissolved. The fenbendazole is then added and the mixture is stirred until it is homogeneous.
The mixture is then passed through a homogenizer to obtain relatively uniform particle size distribution on the order of about 1 micron (m). The homogenization is carried out by means known in the art such as for example with a rotor stator or a high pressure homogenizer. When using a single head high pressure homogenizer, the mixture is passed through until the pressure can be maintained within the range of from 9,000 to about 15,000 psig, preferably in a range of from about 12,000 psig to about 14,000 psig, most preferably within a range of about 13,000 psig. When using a triple head high pressure homogenizer, the mixture is passed through at a pressure of from about 2,000 psig to about 10,000 psig, preferably within a range of from about 4,000 psig to about 8,000 psig.
The following non-limiting examples are provided to illustrate the methods of preparation of compositions both within and without the compositions of this invention.
EXAMPLE 1
To 1,300 ml of purified water, USP, there was added 40 grams (g) of benzyl alcohol and 200 g of Polysorbate 80 and the mixture was stirred until a complete solution was formed. Then there was added 400 g of fenbendazole and the mixture was stirred until it was homogeneous. Sufficient water was added to bring the total volume to 2,000 ml. Then the mixture was passed twice through a Rannie high pressure homogenizer (Model MINI-LAB, type 8.30 H). During the initial pass through the pressure fluctuated greatly. On the second pass the pressure was maintained between 12,000 psig and 13,000 psig.
EXAMPLE 2
To 1,300 ml of purified water, USP, there was added 40 g of benzyl alcohol and 200 g of Poloxamer 188 (an α-hydro-ω-hydroxypoly(oxyethylene)poly-(oxypropylene)poly(oxyethylene) block copolymer) and the mixture was stirred until a complete solution was formed. Then there was added 400 g of fenbendazole and the mixture was stirred until it was homogeneous. Sufficient water was added to bring the total volume to 2,000 ml. Then the mixture was passed twice through a Rannie high pressure homogenizer (Model MINI-LAB, type 8.304), first at 8,000 to 10,000 psig and then at 13,500 psig.
The formulations of the invention were evaluated as follows:
One drop of suspension was placed in 10 ml of water and the samples were shaken on an Eberbach shaker for 1 minute and then removed. The samples were then stored at -10°C, room temperature and 55°C for three months and then examined for viscosity and particle size. Additionally, the samples were examined at 24 hours to see if the particles were still in suspension. The results for Examples 1 and 2 are set forth in Table 1.
Example No. Temperature °C Viscosity Particle Size Suspension after 24 Hours
1 RT Low Normal YES
55 Low Normal YES
-10 Low Normal YES
2 RT Low Normal NO
55 Low Normal NO
-10 Low Normal NO
EXAMPLE 3
To 3,750 ml of purified water, USP there was added 1,000 g of Polysorbate 80, NF and 50 g of simethicone emulsion, USP and the mixture was stirred until it was homogeneous. Then there was added 200 g of benzyl alcohol, NF and 2,000 g of fenbendazole and the mixture was stirred until it was homogeneous, following which an additional 4,097.5 ml of purified water, USP was added while mixing. Mixing was continued until the mixture was homogeneous.
The suspension was divided into 7 portions, A through G. Portions B to G were homogenized each using a different homogenizer or different processing conditions. The viscosity of each portion was measured with a Brookfiled viscometer model RVTI, Spindle HRVI, speed 5 rpm. In addition the particle size distribution was determined by the Galai ClS-1 automated particle size analyzer with a 1° wedge prism installed in the 0-60 M range. Each sample was analyzed four times and the results were averaged. The processing conditions for each sample are set forth in Table 2 along with the viscosity data for each portion.
Sample Processing Viscosity
A No Additional Processing 40 cps
B Arde-Barinco 30 minutes at setting 25 34 cps
C Union Homogenizer HTDI 1 pass at 2,000 psi 50 cps
D Union Homogenizer HTDl 1 pass at 4,000 psi 60 cps
E Union Homogenizer HTDl 1 pass at 6,000 psi 70 cps
F Union Homogenizer HTDl 1 pass at 8,000 psi 96 cps
G Union Homogenizer HTD1 2 passes at 8,000 psi 126 cps

Claims (13)

  1. A stable aqueous suspension for drinking water administration characterized in that it comprises 10 to 30% by weight of fenbendazole, 5 to 15% by weight of a water soluble nonionic surface active agent comprised of complex esters and ester-ethers derived from hexahydric alcohols, alkylene oxides and fatty acids by adding polyoxyethylene chains to hydroxyl of sorbitol and hexitrol anhydrides (hexitrans and hexides) derived from sorbitol and than partially esterifying with said fatty acids such as lauric, palmitic, stearic and oleic, 1 to 3% by weight of a preservative and water.
  2. A suspension according to claim 1 characterized in that the water soluble nonionic surface agent is a Tween type product (polysorbate).
  3. A suspension according to claim 2 characterized in that the Tween type product is polyoxyethylene (20) sorbitan monoleate (Polysorbate 80).
  4. A suspension according to claim 1 to 3 characterized in that the preservative is an arylalkyl alcohol.
  5. A suspension according to claim 1 to 4 characterized in that it additionally comprises an antifoaming agent.
  6. A suspension according to claim 5 characterized in that the antifoaming agent is simethecone emulsion USP.
  7. A suspension according to claim 1 to 6 characterized in that it comprises 15 to 25% fenbendazole by weight, 7.5 to 12.5% of the water soluble nonionic surface agent by weight and 1.5 to 2.5 % of a preservative by weight.
  8. A suspension according to claim 7 characterized in that it comprises 20% of fenbendazole by weight, 10 % of the water soluble nonionic surface agent by weight and 2 % of a preservative by weight.
  9. A suspension according to claim 1 to 8 characterized in that it is diluted with water to a concentration of 4,000 ppm to 12,000 ppm of fenbendazole by weight, 2,000 ppm to 6,000 ppm of the water soluble nonionic surface agent by weight and 400 ppm to 1,200 ppm of a preservative by weight.
  10. A suspension according to claim 9 characterized in that it comprises 6,000 ppm to 10,000 ppm of fenbendazole by weight, 3,000 ppm to 5,000 ppm of the water soluble nonionic surface agent by weight and 600 ppm to 1,000 ppm of a preservative by weight.
  11. A suspension according to claim 10 characterized in that it comprises 8,000 ppm of fenbendazole by weight, 4,000 ppm of the water soluble nonionic surface agent by weight and 500 ppm of a preservative by weight.
  12. A suspension according to claim 1 to 11 characterized in that it is diluted with water to a concentration of 45 ppm to 80 ppm of fenbendazole by weight.
  13. Use of the suspension according to any of the preceding claims for the manufacture of a medicament for the control of parasites in animals after administration via the drinking water route.
EP95901776A 1993-11-10 1994-11-09 Fenbendazole formulations Expired - Lifetime EP0727996B1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US08/149,877 US5538989A (en) 1993-11-10 1993-11-10 Fenbendazole formulations
PCT/US1994/012712 WO1995013065A1 (en) 1993-11-10 1994-11-09 Fenbendazole formulations
US149877 1998-09-08

Publications (3)

Publication Number Publication Date
EP0727996A1 EP0727996A1 (en) 1996-08-28
EP0727996A4 EP0727996A4 (en) 1996-11-06
EP0727996B1 true EP0727996B1 (en) 2002-08-07

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EP95901776A Expired - Lifetime EP0727996B1 (en) 1993-11-10 1994-11-09 Fenbendazole formulations

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US (1) US5538989A (en)
EP (1) EP0727996B1 (en)
JP (1) JP3523260B2 (en)
KR (1) KR960705563A (en)
AT (1) ATE221780T1 (en)
BR (1) BR9408023A (en)
CA (1) CA2176223C (en)
DE (1) DE69431162T2 (en)
DK (1) DK0727996T3 (en)
ES (1) ES2181763T3 (en)
MY (1) MY115429A (en)
PH (1) PH31320A (en)
PT (1) PT727996E (en)
WO (1) WO1995013065A1 (en)

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US11564910B2 (en) 2017-12-08 2023-01-31 Adamis Pharmaceuticals Corporation Drug compositions
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CN116602964B (en) * 2023-07-18 2023-09-22 山东国邦药业有限公司 Fenbendazole powder and preparation method and application thereof

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PT727996E (en) 2002-11-29
US5538989A (en) 1996-07-23
EP0727996A4 (en) 1996-11-06
CA2176223A1 (en) 1995-05-18
CA2176223C (en) 2003-02-11
ES2181763T3 (en) 2003-03-01
DE69431162T2 (en) 2002-12-12
KR960705563A (en) 1996-11-08
PH31320A (en) 1998-07-06
EP0727996A1 (en) 1996-08-28
JPH09506086A (en) 1997-06-17
DK0727996T3 (en) 2002-11-18
ATE221780T1 (en) 2002-08-15
DE69431162D1 (en) 2002-09-12
BR9408023A (en) 1996-12-10
JP3523260B2 (en) 2004-04-26
WO1995013065A1 (en) 1995-05-18
MY115429A (en) 2003-06-30

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